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Mol. Cell. Biol. doi:10.1128/MCB.00195-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Undamaged DNA Transmits and Enhances DNA Damage Checkpoint Signals in Early Embryos

Howard Hughes Medical Institute and Department of Pharmacology, University of, Colorado School of Medicine, Aurora, Colorado 80045, USA

^* To whom correspondence should be addressed. Email: jim.maller{at}uchsc.edu.

	Abstract

In Xenopus embryos, the midblastula transition (MBT) at the 12^th cell division marks initiation of critical developmental events, including zygotic transcription and the abrupt inclusion of gap phases into cell cycle. Interestingly, although an ionizing radiation induced checkpoint response is absent in pre-MBT embryos, introduction of a threshold amount of undamaged plasmid or sperm DNA allows a DNA damage checkpoint response to be activated. We show here that undamaged threshold DNA directly participates in checkpoint signaling, as judged by several dynamic changes, including H2AX phosphorylation, ATM phosphorylation and loading onto chromatin, and Chk1/Chk2 phosphorylation and release from nuclear DNA. These responses on physically separate threshold DNA require g-H2AX and are triggered by an ATM-dependent soluble signal initiated by damaged DNA. The signal persists in egg extracts even after damaged DNA is removed from the system, indicating the absence of damaged DNA is not sufficient to end the checkpoint response. The results identify a novel mechanism by which undamaged DNA enhances checkpoint signaling, and provide an example of how the transition to cell cycle checkpoint activation during development is accomplished by maternally programmed increases in the DNA-to-cytoplasmic ratio.